RESUMO
Available online Atopic dermatitis (AD) is a chronic, persistent inflammatory skin disease characterized by eczema-like lesions and itching. Although topical steroids have been reported for treating AD, they are associated with adverse effects. Thus, safer medications are needed for those who cannot tolerate these agents for long periods. Mangiferin (MAN) is a flavonoid widely found in many herbs, with significant anti-inflammatory and immunomodulatory activities. However, the potential modulatory effects and mechanisms of MAN in treating Th2 inflammation in AD are unknown. In the present study, we reported that MAN could reduce inflammatory cell infiltration and scratching at the lesion site by decreasing MC903-induced levels of Th2-type cytokines, Histamine, thymic stromal lymphopoietin, Leukotriene B4, and immunoglobulin E. The mechanism may be related to reductions in MAPK and NF-κB-associated protein phosphorylation by macrophages. The results suggested that MAN may be a promising therapeutic agent for AD.
Assuntos
Citocinas , Dermatite Atópica , Macrófagos , NF-kappa B , Células Th2 , Xantonas , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/imunologia , Xantonas/farmacologia , Xantonas/uso terapêutico , Animais , NF-kappa B/metabolismo , Células Th2/imunologia , Células Th2/efeitos dos fármacos , Citocinas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos , Humanos , Masculino , Linfopoietina do Estroma do Timo , Imunoglobulina E/metabolismo , Pele/efeitos dos fármacos , Pele/patologia , Pele/imunologia , Pele/metabolismoRESUMO
With the abuse of antibiotics and azoles, drug-resistant Candida albicans infections have increased sharply and are spreading rapidly, thereby significantly reducing the antifungal efficacy of existing therapeutics. Several patients die of fungal infections every year. Therefore, there is an urgent requirement to develop new drugs. Accordingly, we synthesized a series of polypyridyl ruthenium (II) complexes having the formula [Ru (NN)2 (bpm)] (PF6)2 (N-N = 2,2'-bipyridine) (bpy, in Ru1), 1,10-phenanthroline (phen, in Ru2), 4,7-diphenyl-1,10-phenanthroline (DIP, in Ru3) (bpm = 2,2'-bipyrimidine) and studied their antifungal activities. Ru3 alone had no effect on the drug-resistant strains, but Ru3 combined with fluconazole (FLC) exhibited significant antifungal activity on drug-resistant strains. A high-dose combination of Ru3 and FLC exhibited direct fungicidal activity by promoting the accumulation of reactive oxygen species and damaging the cellular structure of C. albicans. Additionally, the combination of Ru3 and FLC demonstrated potent antifungal efficacy in vivo in a mouse model of invasive candidiasis. Moreover, the combination significantly improved the survival state of mice, restored their immune systems, and reduced renal injury. These findings could provide ideas for the development of ruthenium (II) complexes as novel antifungal agents for drug-resistant microbial stains.
Assuntos
Candidíase , Rutênio , Humanos , Animais , Camundongos , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Candida albicans , Rutênio/farmacologia , Candidíase/tratamento farmacológico , Testes de Sensibilidade MicrobianaRESUMO
Ovarian cancer is a common, highly lethal tumor. Herein, we reported that S-phase kinase-associated protein 2 (Skp2) is essential for the growth and aerobic glycolysis of ovarian cancer cells. Skp2 was upregulated in ovarian cancer tissues and associated with poor clinical outcomes. Using a customized natural product library screening, we found that xanthohumol inhibited aerobic glycolysis and cell viability of ovarian cancer cells. Xanthohumol facilitated the interaction between E3 ligase Cdh1 and Skp2 and promoted the Ub-K48-linked polyubiquitination of Skp2 and degradation. Cdh1 depletion reversed xanthohumol-induced Skp2 downregulation, enhancing HK2 expression and glycolysis in ovarian cancer cells. Finally, a xenograft tumor model was employed to examine the antitumor efficacy of xanthohumol in vivo. Collectively, we discovered that xanthohumol promotes the binding between Skp2 and Cdh1 to suppress the Skp2/AKT/HK2 signal pathway and exhibits potential antitumor activity for ovarian cancer cells.
Assuntos
Flavonoides , Glicólise , Neoplasias Ovarianas , Propiofenonas , Proteínas Quinases Associadas a Fase S , Ubiquitinação , Propiofenonas/farmacologia , Proteínas Quinases Associadas a Fase S/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Flavonoides/farmacologia , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Glicólise/efeitos dos fármacos , Animais , Transdução de Sinais/efeitos dos fármacos , Caderinas/metabolismo , Carcinogênese/efeitos dos fármacos , Antígenos CD/metabolismo , Hexoquinase/metabolismo , Linhagem Celular Tumoral , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Fitoterapia , Camundongos Nus , Antineoplásicos Fitogênicos/farmacologiaRESUMO
Leprosy and psoriasis rarely coexist, the specific molecular mechanisms underlying their mutual exclusion have not been extensively investigated. This study aimed to reveal the underlying mechanism responsible for the mutual exclusion between psoriasis and leprosy. We obtained leprosy and psoriasis data from ArrayExpress and GEO database. Differential expression analysis was conducted separately on the leprosy and psoriasis using DEseq2. Differentially expressed genes (DEGs) with opposite expression patterns in psoriasis and leprosy were identified, which could potentially involve in their mutual exclusion. Enrichment analysis was performed on these candidate mutually exclusive genes, and a protein-protein interaction (PPI) network was constructed to identify hub genes. The expression of these hub genes was further validated in an external dataset to obtain the critical mutually exclusive genes. Additionally, immune cell infiltration in psoriasis and leprosy was analyzed using single-sample gene set enrichment analysis (ssGSEA), and the correlation between critical mutually exclusive genes and immune cells was also examined. Finally, the expression pattern of critical mutually exclusive genes was evaluated in a single-cell transcriptome dataset. We identified 1098 DEGs in the leprosy dataset and 3839 DEGs in the psoriasis dataset. 48 candidate mutually exclusive genes were identified by taking the intersection. Enrichment analysis revealed that these genes were involved in cholesterol metabolism pathways. Through PPI network analysis, we identified APOE, CYP27A1, FADS1, and SOAT1 as hub genes. APOE, CYP27A1, and SOAT1 were subsequently validated as critical mutually exclusive genes on both internal and external datasets. Analysis of immune cell infiltration indicated higher abundance of 16 immune cell types in psoriasis and leprosy compared to normal controls. The abundance of 6 immune cell types in psoriasis and leprosy positively correlated with the expression levels of APOE and CYP27A1. Single-cell data analysis demonstrated that critical mutually exclusive genes were predominantly expressed in Schwann cells and fibroblasts. This study identified APOE, CYP27A1, and SOAT1 as critical mutually exclusive genes. Cholesterol metabolism pathway illustrated the possible mechanism of the inverse association of psoriasis and leprosy. The findings of this study provide a basis for identifying mechanisms and therapeutic targets for psoriasis.
Assuntos
Artrogripose , Hanseníase , Psoríase , Humanos , Hanseníase/genética , Psoríase/genética , Colesterol , Apolipoproteínas E , Biologia ComputacionalRESUMO
Numerous studies have supported that nonalcoholic fatty liver disease (NAFLD) is highly associated with gut microbiota dysbiosis. Ling-Gui-Zhu-Gan decoction (LG) has been clinically used to treat NAFLD, but the underlying mechanism remains unknown. This study investigated the therapeutic effect and mechanisms of LG in mice with NAFLD induced by a high-fat diet (HD). An HD-induced NAFLD mice model was established to evaluate the efficacy of LG followed by biochemical and histopathological analysis. Metagenomics, metabolomics, and transcriptomics were used to explore the structure and metabolism of the gut microbiota. LG significantly improved hepatic function and decreased lipid droplet accumulation in HD-induced NAFLD mice. LG reversed the structure of the gut microbiota that is damaged by HD and improved intestinal barrier function. Meanwhile, the LG group showed a lower total blood bile acids (BAs) concentration, a shifted BAs composition, and a higher fecal short-chain fatty acids (SCFAs) concentration. Furthermore, LG could regulate the hepatic expression of genes associated with the primary BAs biosynthesis pathway and peroxisome proliferator-activated receptor (PPAR) signaling pathway. Our study suggested that LG could ameliorate NAFLD by altering the structure and metabolism of gut microbiota, while BAs and SCFAs are considered possible mediating substances. IMPORTANCE: Until now, there has still been no study on the gut microbiota and metabolomics of Ling-Gui-Zhu-Gan decoction (LG) in nonalcoholic fatty liver disease (NAFLD) mouse models. Our study is the first to report on the reshaping of the structure and metabolism of the gut microbiota by LG, as well as explore the potential mechanism underlying the improvement of NAFLD. Specifically, our study demonstrates the potential of gut microbial-derived short-chain fatty acids (SCFAs) and blood bile acids (BAs) as mediators of LG therapy for NAFLD in animal models. Based on the results of transcriptomics, we further verified that LG attenuates NAFLD by restoring the metabolic disorder of BAs via the up-regulation of Fgf15/FXR in the ileum and down-regulation of CYP7A1/FXR in the liver. LG also reduces lipogenesis in NAFLD mice by mediating the peroxisome proliferator-activated receptor (PPAR) signaling pathway, which then contributes to reducing hepatic inflammation and improving intestinal barrier function to treat NAFLD.
Assuntos
Dieta Hiperlipídica , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Camundongos , Masculino , Dieta Hiperlipídica/efeitos adversos , Disbiose/tratamento farmacológico , Disbiose/microbiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Ácidos e Sais Biliares/metabolismo , Ácidos Graxos Voláteis/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Extratos VegetaisRESUMO
NASH (non-alcoholic steatohepatitis) is a severe liver disease characterized by hepatic chronic inflammation that can be associated with the gut microbiota. In this study, we explored the therapeutic effect of Gynostemma pentaphyllum extract (GPE), a Chinese herbal extract, on methionine- and choline-deficient (MCD) diet-induced NASH mice. Based on the peak area, the top ten compounds in GPE were hydroxylinolenic acid, rutin, hydroxylinoleic acid, vanillic acid, methyl vanillate, quercetin, pheophorbide A, protocatechuic acid, aurantiamide acetate, and iso-rhamnetin. We found that four weeks of GPE treatment alleviated hepatic confluent zone inflammation, hepatocyte lipid accumulation, and lipid peroxidation in the mouse model. According to the 16S rRNA gene V3-V4 region sequencing of the colonic contents, the gut microbiota structure of the mice was significantly changed after GPE supplementation. Especially, GPE enriched the abundance of potentially beneficial bacteria such as Akkerrmansia and decreased the abundance of opportunistic pathogens such as Klebsiella. Moreover, RNA sequencing revealed that the GPE group showed an anti-inflammatory liver characterized by the repression of the NF-kappa B signaling pathway compared with the MCD group. Ingenuity Pathway Analysis (IPA) also showed that GPE downregulated the pathogen-induced cytokine storm pathway, which was associated with inflammation. A high dose of GPE (HGPE) significantly downregulated the expression levels of the tumor necrosis factor-α (TNF-α), myeloid differentiation factor 88 (Myd88), cluster of differentiation 14 (CD14), and Toll-like receptor 4 (TLR4) genes, as verified by real-time quantitative PCR (RT-qPCR). Our results suggested that the therapeutic potential of GPE for NASH mice may be related to improvements in the intestinal microenvironment and a reduction in liver inflammation.